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Gene Review

PYGM  -  phosphorylase, glycogen, muscle

Homo sapiens

Synonyms: Glycogen phosphorylase, muscle form, Myophosphorylase
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Disease relevance of PYGM

  • We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically [1].
  • To clarify these issues, DNA extracted from archival tissue from 25 type I carcinoids, 4 type III carcinoids, and 2 neuroendocrine carcinomas was amplified by PCR, using primers for six polymorphic markers located on chromosome 11q13 (PYGM, D11S4946, and D11S913) and 11q14 (D11S916, D11S901, and D11S1365), for analysis of LOH [2].
  • Infrequent (< or =12%) or absent LOH was detected at the remaining loci, including several loci commonly mutated in breast cancer (i.e., INT2, PYGM, and NM23) [3].
  • Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387 insA/del 8 bp) in the PYGM gene causing McArdle's disease [4].
  • DNA of blood and tumoral sections from two patients with adrenal myelolipoma were analyzed by examination of variable number of tandem repeats (VNTR) loci PYGM, D11S987, D11S480, and D11S449 on chromosome 11q13 and by complete direct DNA sequencing of all coding exons and splice junctions of the MEN-I gene [5].

High impact information on PYGM


Chemical compound and disease context of PYGM


Biological context of PYGM

  • Localization of the photoreceptor gene ROM1 to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM [14].
  • The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus [15].
  • Loss of heterozygosity studies in MEN 1 and sporadic tumors suggest that the MEN1 gene encodes a tumor suppressor and have helped to narrow the location of the gene to a 600-kb interval between PYGM and D11S449 [16].
  • Of these, two (137C7A, 137C7B) were derived from PYGM-containing BAC (bacterial artificial chromosome-137C7) sequences, one from INT2-containing cosmid sequences and the marker D11S4748, a (CA)20 repeat marker that was developed by us [17].
  • We report two siblings with McArdle's disease who are both compound heterozygotes for two non-identical frameshift mutations in the PYGM gene; a previously reported 753 delA in exon 18 and a novel 387 insA/del 8 bp in exon 10 [4].

Anatomical context of PYGM


Associations of PYGM with chemical compounds

  • This homozygous T-to-C transition results in the replacement of a highly conserved tryptophan at amino acid position (aa) 797 with an arginine in the C-terminal domain of the PYGM protein [22].
  • This homozygous C-to-A mutation results in the replacement of a highly conserved alanine at amino acid position 659 with an aspartic acid in the C-terminal domain of the myophosphorylase gene protein, near binding sites for pyridoxal phosphate and glucose [23].
  • Expression of muscle-type phosphorylase in innervated and aneural cultured muscle of patients with myophosphorylase deficiency [24].
  • Carnitine palmityl transferase deficiency may be more common than previously supposed, may be in part amenable to dietary therapy, can be easily distinguished from myophosphorylase deficiency, and may provide insight into the metabolism of fatty acids and ketone bodies as well as energy requirements of skeletal muscle [25].
  • Activation of phosphorylase by cyclic AMP-dependent protein kinase was inhibited by antibodies to normal human myophosphorylase or by inhibitory protein to cyclic AMP-dependent protein kinase [26].

Other interactions of PYGM

  • The locus for MEN1 is tightly linked to the marker PYGM on chromosome 11q13, and linkage analysis places the MEN1 gene within a 2-Mb interval flanked by the markers D11S1883 and D11S449 [16].
  • TCN1, PGA, and PYGM did not yield any comigrating fragments and could not be physically linked on this PFGE map [27].
  • Using highly polymorphic markers, we have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM [28].
  • Two patients showed a defect of PPL in muscle, and were homozygous for the most common mutation associated with McArdle's disease, R49X in the muscle PPL gene (PYGM) [29].
  • Linkage analysis of the Venezuelan reference pedigree places GSTP1 5 cM distal to PYGM and 4 cM proximal to FGF3 thereby providing a genetic marker half-way between these two loci [30].

Analytical, diagnostic and therapeutic context of PYGM


  1. Somatic mutations in MEN type 1 tumors, consistent with the Knudson "two-hit" hypothesis. Pannett, A.A., Thakker, R.V. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  2. Loss of heterozygosity in 11q13-14 regions in gastric neuroendocrine tumors not associated with multiple endocrine neoplasia type 1 syndrome. D'Adda, T., Keller, G., Bordi, C., Höfler, H. Lab. Invest. (1999) [Pubmed]
  3. Loss of heterozygosity is detected at chromosomes 1p35-36 (NB), 3p25 (VHL), 16p13 (TSC2/PKD1), and 17p13 (TP53) in microdissected apocrine carcinomas of the breast. Lininger, R.A., Zhuang, Z., Man, Y., Park, W.S., Emmert-Buck, M., Tavassoli, F.A. Mod. Pathol. (1999) [Pubmed]
  4. Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387 insA/del 8 bp) in the PYGM gene causing McArdle's disease. Martín, M.A., Rubio, J.C., García, A., Fernández, M.A., Campos, Y., Krawczak, M., Cooper, D.N., Arenas, J. Clin. Genet. (2001) [Pubmed]
  5. Complete sequencing and mRNA expression analysis of the MEN-I gene in adrenal myelolipoma. Schulte, K.M., Heinze, M., Mengel, M., Scheuring, S., Köhrer, K., Röher, H.D. Horm. Metab. Res. (2000) [Pubmed]
  6. Bardet-Biedl syndrome is linked to DNA markers on chromosome 11q and is genetically heterogeneous. Leppert, M., Baird, L., Anderson, K.L., Otterud, B., Lupski, J.R., Lewis, R.A. Nat. Genet. (1994) [Pubmed]
  7. Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). Tsujino, S., Shanske, S., DiMauro, S. N. Engl. J. Med. (1993) [Pubmed]
  8. Increased myophosphorylase a in malignant hyperthermia. Willner, J.H., Wood, D.S., Cerri, C., Britt, B. N. Engl. J. Med. (1980) [Pubmed]
  9. Do carriers of PYGM mutations have symptoms of McArdle disease? Andersen, S.T., Dunø, M., Schwartz, M., Vissing, J. Neurology (2006) [Pubmed]
  10. Reflex sympathetic activation during static exercise is severely impaired in patients with myophosphorylase deficiency. Fadel, P.J., Wang, Z., Tuncel, M., Watanabe, H., Abbas, A., Arbique, D., Vongpatanasin, W., Haley, R.W., Victor, R.G., Thomas, G.D. J. Physiol. (Lond.) (2003) [Pubmed]
  11. ATP degradation products after ischemic exercise: hereditary lack of phosphorylase or carnitine palmityltransferase. Bertorini, T.E., Shively, V., Taylor, B., Palmieri, G.M., Fox, I.H. Neurology (1985) [Pubmed]
  12. Myophosphorylase deficiency: two different molecular etiologies. Feit, H., Brooke, M.H. Neurology (1976) [Pubmed]
  13. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Vorgerd, M., Grehl, T., Jager, M., Muller, K., Freitag, G., Patzold, T., Bruns, N., Fabian, K., Tegenthoff, M., Mortier, W., Luttmann, A., Zange, J., Malin, J.P. Arch. Neurol. (2000) [Pubmed]
  14. Localization of the photoreceptor gene ROM1 to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM. Bascom, R.A., García-Heras, J., Hsieh, C.L., Gerhard, D.S., Jones, C., Francke, U., Willard, H.F., Ledbetter, D.H., McInnes, R.R. Am. J. Hum. Genet. (1992) [Pubmed]
  15. Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene. Kas, K., Weber, G., Merregaert, J., Michiels, L., Sandelin, K., Skogseid, B., Thompson, N., Nordenskjöld, M., Larsson, C., Friedman, E. Hum. Mol. Genet. (1993) [Pubmed]
  16. A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus. Guru, S.C., Agarwal, S.K., Manickam, P., Olufemi, S.E., Crabtree, J.S., Weisemann, J.M., Kester, M.B., Kim, Y.S., Wang, Y., Emmert-Buck, M.R., Liotta, L.A., Spiegel, A.M., Boguski, M.S., Roe, B.A., Collins, F.S., Marx, S.J., Burns, L., Chandrasekharappa, S.C. Genome Res. (1997) [Pubmed]
  17. Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13. Chakrabarti, R., Srivatsan, E.S., Wood, T.F., Eubanks, P.J., Ebrahimi, S.A., Gatti, R.A., Passaro, E., Sawicki, M.P. Genes Chromosomes Cancer (1998) [Pubmed]
  18. Localization of the genetic defect in multiple endocrine neoplasia type 1 within a small region of chromosome 11. Nakamura, Y., Larsson, C., Julier, C., Byström, C., Skogseid, B., Wells, S., Oberg, K., Carlson, M., Taggart, T., O'Connell, P. Am. J. Hum. Genet. (1989) [Pubmed]
  19. The germinal center kinase gene and a novel CDC25-like gene are located in the vicinity of the PYGM gene on 11q13. Kedra, D., Seroussi, E., Fransson, I., Trifunovic, J., Clark, M., Lagercrantz, J., Blennow, E., Mehlin, H., Dumanski, J. Hum. Genet. (1997) [Pubmed]
  20. Diagnosis of McArdle's disease by molecular genetic analysis of blood. el-Schahawi, M., Tsujino, S., Shanske, S., DiMauro, S. Neurology (1996) [Pubmed]
  21. Myophosphorylase gene transfer in McArdle's disease myoblasts in vitro. Pari, G., Crerar, M.M., Nalbantoglu, J., Shoubridge, E., Jani, A., Tsujino, S., Shanske, S., DiMauro, S., Howell, J.M., Karpati, G. Neurology (1999) [Pubmed]
  22. A missense mutation W797R in the myophosphorylase gene in a Spanish patient with McArdle's disease. Rubio, J.C., Martín, M.A., Campos, Y., Auciello, R., Cabello, A., Arenas, J. Muscle Nerve (2000) [Pubmed]
  23. A homozygous missense mutation (A659D) in the myophosphorylase gene in a Spanish patient with McArdle's disease. Martín, M.A., Rubio, J.C., Campos, Y., Ricoy, J.R., Cabello, A., Arenas, J. Neuromuscul. Disord. (2000) [Pubmed]
  24. Expression of muscle-type phosphorylase in innervated and aneural cultured muscle of patients with myophosphorylase deficiency. Martinuzzi, A., Vergani, L., Carrozzo, R., Fanin, M., Bartoloni, L., Angelini, C., Askanas, V., Engel, W.K. J. Clin. Invest. (1993) [Pubmed]
  25. Recurrent myoglobinuria due to muscle carnitine palmityl transferase deficiency. Reza, M.J., Kar, N.C., Pearson, C.M., Kark, R.A. Ann. Intern. Med. (1978) [Pubmed]
  26. Phosphorylation of McArdle phosphorylase induces activity. Cerri, C.G., Willner, J.H. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  27. A pulsed-field gel electrophoresis (PFGE) map of twelve loci on chromosome 11q11-q13. Petty, E.M., Arnold, A., Marx, S.J., Bale, A.E. Genomics (1993) [Pubmed]
  28. Refining the locus for Best vitelliform macular dystrophy and mutation analysis of the candidate gene ROM1. Nichols, B.E., Bascom, R., Litt, M., McInnes, R., Sheffield, V.C., Stone, E.M. Am. J. Hum. Genet. (1994) [Pubmed]
  29. Molecular analysis of Spanish patients with AMP deaminase deficiency. Rubio, J.C., Martín, M.A., Del Hoyo, P., Bautista, J., Campos, Y., Segura, D., Navarro, C., Ricoy, J.R., Cabello, A., Arenas, J. Muscle Nerve (2000) [Pubmed]
  30. Genetic and radiation-reduced somatic cell hybrid sublocalization of the human GSTP1 gene. Smith, C.M., Bora, P.S., Bora, N.S., Jones, C., Gerhard, D.S. Cytogenet. Cell Genet. (1995) [Pubmed]
  31. McArdle's disease with late-onset symptoms: case report and review of the literature. Felice, K.J., Schneebaum, A.B., Jones, H.R. J. Neurol. Neurosurg. Psychiatr. (1992) [Pubmed]
  32. McArdle's disease: a study on the molecular basis of two different etiologies of myophosphorylase deficiency. Koster, J.F., Slee, R.G., Jennekens, F.G., Wintzen, A.R., van Berkel, T.J. Clin. Chim. Acta (1979) [Pubmed]
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